The overall goal of this project is to understand how retroviruses adversely affect the central nervous system. We are utilizing the mouse as an animal model and have focused our attention on two coisogenic viruses FrCas, which causes an acute non-inflammatory spongiform encephalomyelopathy, and F43 which is avirulent. The two viruses differ in the sequence of their envelope proteins and studies in previous years revealed that the neurovirulence of FrCas was associated with folding instability of its envelope protein and induction of Endoplasmic Reticulum Stress. It is for these reasons that we now suspect that the brain disease induced by FrCas and related murine retroviruses represents a virus-induced protein folding disease. We previously found that misfolding of the FrCas envelope precursor polyprotein in the ER is a consequence of aberrant disulfide bond formation in the ER and that one of the cysteines involved is located in a CWLC protein disulfide isomerase motif in the Surface Glycoprotein (SU). This motif is normally involved in the formation of a critical disulfide bond between SU and the transmembrane protein (TM). Aberrant disulfide bond formation leads to formation of protein aggregates of heterogeneous size. This protein aggregation appears to be the cause of the ER stress and the consequent Unfolded Protein Response (UPR) induced in cells infected with the virus FrCas. Neither protein aggregation nor ER stress is observed in F43 infected cells. The UPR has been shown by others to encompass both adaptive and cell-death responses and at least in vitro FrCas induces both types of pathways. However, it was observed early on in the study of this cellular stress response, that in the brainstem of FrCas-infected mice, the adaptive components of the UPR were impaired. In 2009 we asked the question whether infection of the brainstem by FrCas specifically suppressed adaptive components of the UPR. The UPR was induced in vivo by intraperitoneal injection of tunicamycin (TM). In mock-infected mice TM induced a brisk upregulation of both BiP, an ER chaperone involved in adaptation to misfolded proteins, as well as CHOP, a transcription factor involved in pro-apoptotic responses. The same type of responses to TM was observed in F43-infected mice. However, in FrCas infected mice, the BiP response to TM was indistinguishable from that of untreated mice, whereas the CHOP response was brisk and indistinguishable from TM treated mock-infected mice. The suppression of the BiP response by FrCas appeared to be organ-specific, since it was not observed in the liver. These results suggest that the cell death observed in FrCas-infected brain is a consequence of a skewing of the UPR in favor of cell death pathways, though the nature of this effect remains to be uncovered.